Psychosis and psychotic disorders are used to describe patients for whom there is a loss of contact with reality.
Psychosis and psychotic disorders can result in a number of symptoms including: hallucinations, where the patient senses things that are not there; delusions, where the patient has beliefs that are not based on reality; problems in clear thinking; and not realising that there is anything wrong with them.
The following list illustrates a number of these disease states, many of which are classified in the “Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, text revision” (DSM-IV-TR) published by the American Psychiatric Association 2000: schizophrenia; schizophreniform disorder (acute schizophrenic episode); schizoaffective disorder; bipolar I disorder (mania, manic disorder, manic-depressive psychosis); bipolar II disorder; major depressive disorder with psychotic feature (psychotic depression); delusional disorders (paranoia); shared psychotic disorder (shared paranoia disorder); brief psychotic disorder (other and unspecified reactive psychosis); psychotic disorder not otherwise specified (unspecified psychosis); paranoid personality disorder; schizoid personality disorder; and schizotypal personality disorder.
Schizophrenia is a complex disease where the sufferer has difficulty in understanding the difference between real and unreal experiences. A patient suffering from schizophrenia also has difficulty in logical thought and responding with normal emotions in social and other situations.
Schizophrenia can take on different types: the catatonic type, where the patient suffers motor disturbances, stupor, negativity, rigidity, agitation, and inability to care for their personal needs and a decreased sensitivity to painful stimuli; the paranoid type, where the patient suffers with delusional thoughts of persecution or of a grandiose nature; anxiety; anger; violence and argumentativeness; and the disorganised type, where the patient is incoherent and displays regressive behaviour, delusions, hallucinations, inappropriate laughter, repetitive mannerisms and social withdrawal.
Patients may also suffer with symptoms of one or more subtype or may have had an abatement of the prominent symptoms but some features such as hallucinations may remain.
Schizophreniform disorder (acute schizophrenic episode) is characterized by the presence of some of the symptoms of schizophrenia including: delusions, hallucinations, disorganised speech, disorganised or catatonic behaviour, and negative symptoms. The disorder—including its prodromal, active, and residual phases—lasts longer than 1 month but less than 6 months.
Schizoaffective disorder symptoms can vary greatly from patient to patient. Many patients suffer with problems with mood, daily function or intrusive thoughts. Other symptoms can include elevated, inflated or depressed mood; irritability and poor temper control; changes in appetite, energy and sleep; hallucinations (particularly auditory hallucinations); delusions of reference; paranoia; deteriorating concern with hygiene and disorganised or illogical speech.
Schizoaffective disorder features cycles of severe symptoms followed by improvement.
Bipolar I disorder (mania, manic disorder, manic-depressive psychosis) is characterised by mood swings that range from low (feelings of intense depression and despair) to high (feelings of elation, referred to as “mania”) and can be mixed, for example a depressed mood may be combined with restlessness and overactivity. Often both depressive and manic episodes are experienced.
Bipolar II disorder is characterised by hypomanic episodes as well as at least one major depressive episode. Hypomanic episodes do not go to the extremes of mania (i.e. do not cause social or occupational impairment, and are without psychotic features). Bipolar II is much more difficult to diagnose, since the hypomanic episodes may simply appear as a period of successful high productivity and is reported less frequently than a distressing depression. Psychosis can occur in manic and major depressive episodes, but not in hypomania. For both disorders, there are a number of specifiers that indicate the presentation and course of the disorder, including “chronic”, “rapid cycling”, “catatonic” and “melancholic”.
Major depressive disorder with psychotic feature (psychotic depression) is characterised in that a patient in addition to suffering from depressive symptoms also suffers from hallucinations or delusions. These patients often become paranoid and may believe that their thoughts are not their own or that others can ‘hear’ their thoughts.
Delusional disorders (paranoia) are a form of psychosis where the patient has long-lasting paranoid delusions which have no other physical or medical cause. These delusions may also be accompanied by auditory hallucinations.
Shared psychotic disorder (shared paranoia disorder) is a very rare condition in which people close to a mentally ill person share his or her false beliefs (delusions). As an example, a man with schizophrenia may falsely believe that his children are trying to murder him. His wife develops shared psychotic disorder and comes to believe it as well. This disorder usually occurs in long-term relationships and involves two people. However, it can also develop among members of a group, such as within families. It affects women more often than men.
Brief psychotic disorder (other and unspecified reactive psychosis) is characterised by patients who experience an acute psychotic episode lasting longer than one day but less than one month and that may or may not immediately follow an important life stress or a pregnancy (with postpartum onset). This illness usually comes as a surprise as there is no forewarning that the person is likely to break down, although this disorder is more common in people with a pre-existing personality disorder.
Paranoid personality disorder is characterised by an exaggeration of the cognitive modules for sensitivity to rejection, resentfulness, distrust, as well as the inclination to distort experienced events. Neutral and friendly actions of others are often misinterpreted as being hostile or contemptuous. Unfounded suspicions regarding the sexual loyalty of partners and loyalty in general as well as the belief that one's rights are not being recognized is stubbornly and argumentatively insisted upon. Such individuals can possess an excessive self-assurance and a tendency toward an exaggerated self-reference. Pathological jealousy, instinctive aggressive counter-attack, the need to control others, and the gathering of trivial or circumstantial “evidence” to support their jealous beliefs also features.
Schizoid personality disorder (SPD) is characterised by a lack of interest in social relationships, a tendency towards a solitary lifestyle, secretiveness, and emotional coldness. SPD is reasonably rare compared with other personality disorders, its prevalence is estimated at less than 1% of the general population.
Schizotypal personality disorder, is characterized by a need for social isolation, odd behaviour and thinking, and often unconventional beliefs such as being convinced of having extra-sensory abilities.
Psychosis and psychotic disorders are commonly treated with a class of medication known as atypical anti-psychotics.
Atypical anti-psychotics are also known as second or third generation anti-psychotics of which some are approved by the FDA for use in the treatment of psychotic disorders including: schizophrenia; bipolar disorder; mania and other indications.
Atypical anti-psychotics are a heterogeneous group of otherwise unrelated drugs which are grouped as such due to the fact that they work in a different manner to other typical anti-psychotics. Many, but not all atypical anti-psychotics work by acting upon the serotonin and dopamine receptor systems in the brain.
Examples of atypical anti-psychotic medicaments include but are not limited to: aripiprazole; risperidone; paliperidone; ziprasidone; olanzapine; quetiapine; clozapine; sulpiride; amisulpride; iloperidone; cariprazine; asenapine.
Aripiprazole is a third generation antipsychotic. Aripiprazole has activity as an agonist at the serotonin receptors and dopamine receptors, and acts as an agonist or partial agonist at the serotonin 5-HT1A receptor and as an agonist or partial agonist at the dopamine D.sub.2 receptor. Aripiprazole is a dopamine-serotonin system stabilizer.
Anti-psychotic medication is rarely used in children, although recently both risperidone and aripiprazole have received FDA approval for their use in the treatment of schizophrenia and mania or mixed episodes of bipolar disorder in children and adolescents.
The atypical anti-psychotics class of medicaments are most often favoured by physicians in the treatment of psychotic disorders such as schizophrenia, and their use is slowly replacing the use of typical anti-psychotics such as fluphenazine, haloperidol and chlorpromazine.
One characteristic of atypical anti-psychotics is the decreased propensity of these medicaments to cause extrapyramidal side effects in the absence of prolactin elevation.
The side-effects that have been reported for the class of medicaments known as atypical anti-psychotics vary from drug to drug.
The medicaments olanzapine and risperidone have been contra-indicated in elderly patients with dementia due to an increased risk of stroke.
It is also known that atypical anti-psychotics can cause abnormal shifts in sleep patterns and as such result in extreme tiredness and weakness.
Other side effects include tardive dyskinsia (involuntary jerking and facial grimacing), and dystonia (involuntary muscle contractions). In addition some atypical anti-psychotics may cause serious metabolic disorders, similar to those caused by the typical anti-psychotics.
Such metabolic disorders include hyperglycemia and diabetes.
There are also many reports that anti-psychotic drugs lead to a host of side-effects related to the metabolism.
For example, weight gain, insulin resistance, type 1 and 2 diabetes, hyperlipidemia, hyperprolactinemia, and cardiovascular disease are amongst the metabolically related side-effects that patients taking anti-psychotic medication report.
Clearly there is a significant requirement for an efficacious treatment that is able to prevent or treat psychosis or psychotic disorders without resulting in side-effects. In particular the reduction in the incidence of metabolically related side-effects is of great importance as these diseases and conditions can be so disabling that the patient may stop taking their medication in order to alleviate the side-effects.
There are a number of documents which focus on the use of CB1 antagonists in combination with antipsychotics for this purpose.
WO2006/097605 and US 2008/0015186 describe the use of a pyrazole-based cannabinoid receptor (CB1) antagonist, specifically rimonabant, with antipsychotics such as, risperidone, to counter the weight problems, obesity and metabolic disorders associated with the use of such antipsychotics. In other words both drugs independently perform their natural function.
WO2007/136571 relates to the use of CB1 antagonists and inverse agonists in combination with antipsychotic agents.
WO 03/087037 discloses a treatment for mania comprising using a CB1 receptor modulator in combination with an antipsychotic agent.
US2007/0105914 teaches using CB1 receptor modulators in combination with conventional antipsychotic drugs.
WO2005/063761 describes Azabicyclic heterocycles as cannabinoid receptor modulators and suggests these compounds may be used in combination with antipsychotic agents.
WO2005/020992 suggests countering the problem of weight gain associated with many atypical antipsychotics by co-administering a CB1 antagonist.
By and large these documents are speculative in nature suggesting combinations of many different synthetic compounds with little or no support. No one has however specifically investigated using phyto-cannabinoids in combination with antipsychotics.
WO 2006/054057 discloses using the phyto-cannabinoid THCV in the treatment of disease indications associated with the CB1 cannabinoid receptor based on the surprising discovery it is a neutral CB1 antagonist (in contrast to THC which although structurally similar is a CB1 agonist). It suggests using it for the treatment of e.g. obesity and schizophrenia but makes no suggestion of using it in combination with other drugs.
Cannabinoids are a group of chemicals known to activate cannabinoid receptors in cells. These chemicals, which are found in cannabis plants, are also produced endogenously in humans and other animals. These are termed endocannabinoids. Synthetic cannabinoids are chemicals with similar structures to plant cannabinoids or endocannabinoids and it is, of course, possible to also make synthetic versions of these plant cannabinoids or endocannabinoids.
Cannabinoids possess the characteristics of being cyclic molecules exhibiting particular properties such as the ability to easily cross the blood-brain barrier, weak toxicity and few side effects.
Plant cannabinoids or phyto-cannabinoids can also be isolated such that they are “essentially pure” compounds. These isolated cannabinoids are essentially free of the other naturally occurring compounds, such as, other minor cannabinoids and molecules such as terpenes.
Essentially pure compounds have a degree of purity up to at least 95% by total weight. Some essentially pure cannabinoids (whether synthetic or isolated) have been suggested to be neuroprotective agents, either by direct antagonism of the NMDA receptor or by reducing the influx of calcium ions into the cell by another means such as binding with cannabinoid receptors.
However, current thinking is such that it is generally believed that cannabis, and by implication the phyto-cannabinoids, may be responsible for users (particularly juveniles) developing psychological illnesses. This is mainly due to the condition known as cannabis psychosis. Cannabis use has been linked to psychosis by several peer-reviewed studies. A 1987 Swedish study claimed a link between cannabis use and schizophrenia. More recently, the Dunedin Multidisciplinary Health and Development Study published research showing an increased risk of psychosis for cannabis users with a certain genetic predisposition, held by 25% of the population. In 2007, a study published in The Lancet and a poll of mental health experts showed that a growing number of medical health practitioners are convinced that cannabis use increases susceptibility to mental illness, accounting for 14% of the United Kingdom's psychosis cases.
It is likely that the link between cannabis use and psychosis is as a consequence of the high concentration of the psychoactive cannabinoid tetrahydrocannabinol (THC) that is found in most recreational cannabis. 
Despite the strong prejudice against cannabis, the applicant believes there is significant credible evidence supporting the use of certain phyto cannabinoid based medicines in combination with atypical anti-psychotic drugs. The rationale for this is outlined below.
Some plant cannabinoids have been found to be effective agents in the treatment of psychosis or psychotic disorders. For example, the applicant has demonstrated in their co-pending patent application WO 2005/000830 the use of cannabichromene (CBC) type compounds and derivatives in the treatment of mood disorders. The mood disorders to be treated are taken from the group: morbid or clinical depression; unipolar mood disorder; bipolar mood disorder; syndromal depression; panic disorder and anxiety.
Additionally the applicant has also described in their co-pending application PCT/GB2007/0020216 the use of cannabigerol (CBG) type compounds (including cannabigerol propyl analogue (CBGV)) and their derivatives in the treatment of mood disorders. Similarly the mood disorders to be treated are taken from the group: morbid or clinical depression; unipolar mood disorder; bipolar mood disorder; syndromal depression; panic disorder and anxiety.
In addition to the evidence supporting the use of specific cannabinoids in the treatment of psychotic disorders, there is also credible evidence supporting the use of specific cannabinoids to treat a number of diseases or conditions such as for example stroke, diabetes and other metabolic disorders, where use of the atypical anti-psychotic medicaments are contra-indicated.
Thus whilst single cannabinoids might be used in combination with atypical anti-psychotics a preferred approach may be to use combinations of cannabinoids which may or may not be present as a cannabis plant extract. Depending on the extract selected it may desirable to selectively remove all or a proportion of THC or THCA from the extract.